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OBJECTIVECurrent guidelines recommend biennial diabetic retinopathy (DR) screening commencing at the age of 11 years and after 2–5 years’ duration of type 1 diabetes. Growing evidence suggests less frequent screening may be feasible.RESEARCH DESIGN AND METHODSProspective data were collected from 2,063 youth with type 1 diabetes who were screened two or more times between 1990 and 2019. Baseline (mean ± SD) age was 13.3 ± 1.8 years, HbA1c was 8.6 ± 1.3% (70.1 ± 14.7 mmol/mol), diabetes duration was 5.6 ± 2.8 years, and follow-up time was 4.8 ± 2.8 years. DR was manually graded from 7-field retinal photographs using the Early Treatment Diabetic Retinopathy Study (ETDRS) scale. Markov chain was used to calculate probabilities of DR change over time and hazard ratio (HR) of DR stage transition.RESULTSThe incidence of moderate nonproliferative DR (MNPDR) or worse was 8.6 per 1,000 patient-years. Probabilities of transition to this state after a 3-year interval were from no DR, 1.3%; from minimal DR, 5.1%; and from mild DR, 22.2%, respectively. HRs (95% CIs) for transition per 1% current HbA1c increase were 1.23 (1.16–1.31) from no DR to minimal NPDR, 1.12 (1.03–1.23) from minimal to mild NPDR, and 1.28 (1.13–1.46) from mild to MNPDR or worse. HbA1c alone explained 27% of the transitions between no retinopathy and MNPDR or worse. The addition of diabetes duration into the model increased this value to 31% (P = 0.03). Risk was also increased by female sex and higher attained age.CONCLUSIONSThese results support less frequent DR screening in youth with type 1 diabetes without DR and short duration. Although DR progression to advanced stages is generally slow, higher HbA1c greatly accelerates it.

Funding: This work was performed by funding from The University of Sydney (CIA Jenkins) and funds provided by the National Health and Medical Research Council (Australia) APP1147897. Purpose: Robust, affordable plasma proteomic biomarker workflows are needed for large-scale clinical studies. We evaluated aspects of sample preparation to allow LC-MS analysis of more than 1500 samples from the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) trial of adults with type 2 diabetes. Methods: Using LC-MS with data-independent acquisition we evaluated four variables: plasma protein depletion, EDTA or citrated anti-coagulant blood collection tubes, plasma lipid depletion strategies and plasma freeze-thaw cycles. Optimised methods were applied in a pilot study of FIELD participants. Results: LC-MS of undepleted plasma conducted over a 45 min gradient yielded 172 proteins after excluding immunoglobulin isoforms. Cibachrome-blue-based depletion yielded additional proteins but with cost and time expenses, while immunodepleting albumin and IgG provided few additional identifications. Only minor variations were associated with blood collection tube type, delipidation methods and freeze-thaw cycles. From 65 batches involving over 1500 injections, the median intra-batch quantitative differences in the top 100 proteins of the plasma external standard was less than 2%. Fenofibrate altered seven plasma proteins. Conclusions and Clinical Relevance: A robust plasma handling and LC-MS proteomics workflow for abundant plasma proteins has been developed for large-scale biomarker studies that balances proteomic depth with time and resource costs. Publisher PDF

Background: Current guidelines recommend biennial diabetic retinopathy (DR) screening commencing at age of 11years and after 2-5 years duration of type 1 diabetes. Growing evidence suggests less frequent screening may be feasible. Methods: Prospective data were collected from 2,063 youth with type 1 diabetes who were screened ≥2 times between 1990-2019. Baseline (mean±SD) age was 13.3±1.8 years, HbA1c 8.6±1.3% (70.1±14.7 mmol/mol), diabetes duration 5.6±2.8 years and follow-up time 4.8±2.8 years. DR was manually graded from 7-field retinal photographs using the ETDRS scale. Markov chain was used to calculate probabilities of DR change over time and hazard ratio (HR) of DR stage transition. Results: The incidence of moderate non-proliferative DR (MNPDR) or worse was 8.6 per 1000 patient years. Probabilities of transition to this state after 3- years interval were: from no-DR 1.3%; from minimal DR 5.1%; from mild DR 22.2% respectively. HRs (95%CI) for transition per 1% current HbA1c increase were: 1.23 (1.16-1.31) from no-DR to minimal NPDR, 1.12 (1.03-1.23) from minimal to mild NPDR, 1.28 (1.13-1.46) from mild to MNPDR or worse. HbA1c alone explained 27% of the transitions between no-retinopathy and MNPDR or worse. The addition of diabetes duration into the model increased this value to 31% (p=0.03). Risk was also increased by female sex, and higher attained age. Conclusions: These results support less frequent DR screening in youth with type 1 diabetes without DR and short duration. Although DR progression to advanced stages is generally slow, higher HbA1c greatly accelerates it.

The aim of this cross-sectional study was to compare plasma C-peptide presence and levels in people without diabetes (CON) and with Type 1 diabetes and relate C-peptide status to clinical factors. In a subset we evaluated 50 microRNAs (miRs) previously implicated in beta-cell death and associations with clinical status and C-peptide levels. Diabetes age of onset was stratified as adult (≥ 18 y.o) or childhood ( 20 years. Plasma C-peptide was measured by ultrasensitive ELISA. Plasma miRs were quantified using TaqMan probe-primer mix on an OpenArray platform. C-peptide was detectable in 55.3% of (n = 349) people with diabetes, including 64.1% of adults and 34.0% of youth with diabetes, p p p = 0.02, respectively]. In the childhood-onset group more people with longer diabetes duration (> 20 years) had detectable C-peptide (60%) than in those with shorter diabetes duration (39%, p for trend

Background: Mitochondrial DNA (Mt-DNA) copy number (mtDNA-CN) has been proposed as a marker of diabetic kidney disease (DKD) . Most studies are in type 2 diabetes. We determined mtDNA-CN in adults with type 1 diabetes vs. non-diabetic subjects, including associations with complications and risk factors. Methods: Cross-sectional study: 178 T1D adults (mean (SD) age: 38 (14) yrs, 21 (14) yrs T1D, HbA1c: 8.0 (1.5) %, 36% with complications (CX+)) ; 132 non-diabetic adults (CON) (age: 37 (14) yrs, HbA1c: 5.1 (0.4) %) . mtDNA-CN by RT-PCR (ScienCell, Carlsbad, CA) in DNA from whole blood samples. Results: T1D vs. CON: Median (LQ, UQ) mtDNA-CN in T1D vs. CON: 270.8 (189.4, 348.1) vs. 320.5 (264.4, 410.5) ; p Conclusion: T1D per se is associated with lower mtDNA-CN than CON, particularly with DKD. Higher mtDNA-CN in T1D is associated with detectable C-peptide. Age and inflammation related factors are associated with mtDNA-CN. Longitudinal and intervention studies are merited. Disclosure A.S.Januszewski: None. L.Carroll: None. Y.W.Loh: None. D.N.O'neal: None. A.Jenkins: Advisory Panel; Abbott Diabetes, Amgen Inc., Board Member; Insulin for Life , International Diabetes Federation Western Pacific Region, Research Support; JDRF, Medtronic, Mylan N.V., NHMRC Australia.

Diabetes is a major cause of vision loss globally, yet this devastating complication is largely preventable. Early detection and treatment of diabetic retinopathy necessitates screening. Ocular imaging is widely used clinically, both for the screening and management of diabetic retinopathy. Common eye conditions, such as glaucoma, cataracts and retinal vessel thrombosis, and signs of systemic conditions, such as hypertension, are frequently revealed. As well as imaging by a skilled clinician during an eye examination, non‐ophthalmic clinicians, such as general practitioners, endocrinologists, nurses and trained health workers, can also can carry out diabetic eye screening. This process usually comprises local imaging with remote grading, mostly human grading. However, grading incorporating artificial intelligence is emerging. In a clinical research context, retinal vasculature analyses using semi‐automated software in many populations have identified associations between retinal vessel geometry, such as vessel caliber, and the risk of diabetic retinopathy and other chronic complications of type 1 and type 2 diabetes. Similarly, evaluation of corneal nerves by corneal confocal microscopy is revealing diabetes‐related abnormalities, and associations with and predictive power for other chronic diabetes complications. As yet, the value of retinal vessel geometry and corneal confocal microscopy measures at an individual level is uncertain. In this article, targeting non‐ocular clinicians and researchers, we review existent and emerging ocular imaging and grading tools, including artificial intelligence, and their associations between ocular imaging findings and diabetes and its chronic complications., Investigating ocular imaging techniques for analyzing diabetic retinopathy and its complications.

Aims To investigate whether long-term glycemic variability (GV) is associated with vascular complication development in type 2 diabetes. Methods In a post hoc FIELD trial analysis, GV was calculated as the standard deviation and coefficient of variation (CV) of glycated hemoglobin A1c (HbA1c) and fasting plasma glucose. Baseline variables were compared across quartiles of on-study variability by chi square and ANOVA. Prospective associations between baseline to 2-year GV and subsequent vascular and mortality outcomes were analyzed using landmark logistic and Cox proportional hazards regression. Results Baseline factors associated with higher on-study GV included younger age, male gender, longer diabetes duration, and higher pharmacological therapies usage. Both HbA1c and fasting glucose CV were associated with increased risk of microvascular complications (HR 1.02 [95% CI, 1.01-1.03] P < 0.01; and HR 1.01 [95% CI, 1.00-1.01] P < 0.001, respectively). HbA1c and fasting glucose CV were associated with increased cardiovascular disease (HR 1.02 [95% CI, 1.00-1.04]; and HR 1.01 [95% CI, 1.00-1.02], both P < 0.05). HbA1c CV associated with increased stroke (HR 1.03 [95% CI, 1.01-1.06) P < 0.01). Glucose CV associated with increased coronary events (HR 1.01 [95% CI, 1.00-1.02] P < 0.05). Both HbA1c and glucose CV associated with increased total mortality (HR 1.04 [95% CI, 1.02-1.06]; and HR 1.01 [95% CI, 1.01-1.02], both P < 0.001) and noncardiovascular mortality (HR 1.05 [95% CI, (1.03-1.07]; and HR 1.02 [95% CI, 1.01-1.03], both P < 0.001). HbA1c CV associated with coronary mortality (HR 1.04 [95% CI, 1.01-1.07] P < 0.05). Conclusions Long-term GV was associated with increased risk of vascular outcomes in type 2 diabetes.

People with diabetes are at risk of chronic complications and novel biomarkers, such as Advanced glycation end-products (AGEs) may help stratify this risk. We assessed whether plasma low-molecular weight AGEs, also known as LMW-fluorophores (LMW-F), are associated with risk factors, predict complications, and are altered by fenofibrate in adults with type 2 diabetes. Plasma LMW-F were quantified at baseline, after six weeks fenofibrate, and one year post-randomisation to fenofibrate or placebo. LMW-F associations with existing and new composite vascular complications were determined, and effects of fenofibrate assessed. LMW-F correlated positively with age, glycated haemoglobin (HbA1c), pulse pressure, kidney dysfunction and inflammation; and negatively with urate, body mass index, oxidative stress and leptin, albeit weakly (r = 0.04-0.16, all p

To determine whether continuous subcutaneous insulin infusion (CSII) vs. multiple daily injections (MDI) therapy from near-diagnosis of type 1 diabetes is associated with reduced glycaemic variability (GV) and altered microRNA (miRNAs) expression. Adolescents (74% male) within 3-months of diabetes diagnosis (n = 27) were randomized to CSII (n = 12) or MDI. HbA1c, 1-5-Anhydroglucitol (1,5-AG), high sensitivity C-peptide and a custom TaqMan qPCR panel of 52 miRNAs were measured at baseline and follow-up (median (LQ-UQ); 535 (519–563) days). There were no significant differences between groups in baseline or follow-up HbA1c or C-peptide, nor baseline miRNAs. Mean ± SD 1,5-AG improved with CSII vs. MDI (3.1 ± 4.1 vs. − 2.2 ± − 7.0 mg/ml respectively, P = 0.029). On follow-up 11 miRNAs associated with diabetes vascular complications had altered expression in CSII-users. Early CSII vs. MDI use is associated with lower GV and less adverse vascular-related miRNAs. Relationships with future complications are of interest.

The major cause of morbidity and often premature mortality in people with type I diabetes (T1D) is cardiovascular disease owing to accelerated atherosclerosis. We review publications relating to the rationale behind, and clinical tests for, detecting and treating early atherosclerosis in people with T1D. Currently available tools for atherosclerosis assessment include risk equations using vascular risk factors, arterial intima–media thickness, the ankle–brachial index, coronary artery calcification and angiography, and for more advanced lesions, intravascular ultrasound and optical coherence tomography. Evolving research tools include risk equations incorporating novel clinical, biochemical and molecular tests; vascular MRI and molecular imaging. As yet there is little information available to quantify early atherosclerosis. With better means to control the vascular risk factors, such as hypertension, dyslipidaemia and glycaemic control, and emerging therapies to control novel risk factors, further epidemiologic and clinical trials are merited to facilitate the translation into clinical practice of robust means to detect, monitor and treat early atherosclerosis in those with T1D.

Background There is a global concern that physician-researchers are 'a dying breed'. Recent studies of clinical career choices of Australian medical students and doctors have signalled the rising age of medical graduates, generational shifts in work-life attitudes and increased proportion of female graduates. There are scant data regarding Australian physician-researchers. Aims To develop and utilise a questionnaire determining respondent characteristics and 'push' and 'pull' factors for medical graduates to incorporate research into their careers. Methods We developed and administered an 88-item online survey, including quantitative and qualitative questions, to medical students, faculty and alumni of Sydney Medical School, The University of Sydney, asking about their medical career, research experience and interest and reasons for doing or not doing medical research. Responses to all 74 quantitative questions are reported here. Results Data from 427 respondents (44% female; mean ± standard deviation age 38 ± 13 years; 56% completed or undertaking a PhD) were analysed. Attractions of research included a desire to improve human health, intellectual stimulation and career diversity. Barriers included low funding rates, job insecurity and low salaries. Although few were prepared to undertake or recommend full-time research, 71% would recommend part-time research. Respondents perceived a smaller-than-actual gap between clinical and research salaries, and if comparable (75-100% of a clinician's) salaries were available, 89% would like to spend 21-60% of their work time undertaking research. Conclusion Many Australian medical students and doctors are interested in research, especially part time. Perceived obstacles include job insecurity, low funding rates and salary. Respondents underestimated clinical and research salary differences.

Introduction: Excess adipose tissue, esp. with the metabolic syndrome (MetS) promotes development of type 2 diabetes (T2D) and cardiovascular disease (CVD). A major feature of MetS, reduced insulin sensitivity (IS), is associated with increased hepatic lipogenesis, a marker of which is a low SHBG. Features of T2D are increasingly common in T1D. Aim: In T1D adults to determine if SHBG is associated with surrogate measures of IS and MetS. Methods: Cross-sectional analysis of sera from 279 people (Table). Of those with T1D 41 had microvascular complications. SHBG was quantified by chemiluminescent immunoassay (Roche Diagnostics, Mannheim, Germany). IS in T1D was assessed by estimation of M/I by modified published formulae using sex, HDL-C, pulse pressure, T1D duration, waist/height, WHR, BMI and HbA1c. Results: SHBG levels were higher in T1D than in CON and also higher in F vs. M. SHBG levels correlated with age in CON and T1D. M/I in tertile 3 (sex and T1D adjusted) of SHBG was significantly higher vs. tertiles 1 and 2 (in CON and T1D). In T1D SHBG (age and sex adjusted) decreased with increasing number of MetS features. ROC curve for MetS diagnosis in T1D using SHBG had an AUC of 0.73. Conclusion: Taken together these data show that IS and MetS are associated with lower SHBG levels in T1D. We propose a role for SHBG in personalising insulin sensitiser treatment in T1D. Disclosure A. S. Januszewski: None. W. Rankin: None. D. N. O9neal: Advisory Panel; Self; Abbott Diabetes, Medtronic, Sanofi, Research Support; Self; Dexcom, Inc., GlySens Incorporated, Medtronic, Pacific Diabetes Technologies. G. A. Wittert: Advisory Panel; Self; Bayer AG, Research Support; Self; Bayer AG, Speaker9s Bureau; Self; Bayer AG. A. Jenkins: Advisory Panel; Self; Abbott Diabetes, Sanofi-Aventis, Other Relationship; Self; Amgen Inc., Research Support; Self; Abbott, International Diabetes Federation, JDRF, Medtronic, Mylan N. V.

Introduction: The “gold standard” measure of insulin sensitivity (IS), a euglycemic hyperinsulinemic clamp, is costly, time- and labour-intensive. Several formulae, developed using clamp data estimate insulin sensitivity, expressed as estimated glucose disposal rate (eGDR) or insulin sensitivity index (eM/I or elog10M/I). Due to clamp complexity and cost these formulae often lacks independent validation. Aim: To validate several formulae estimating IS using independent euglycaemic hyperinsulinemic clamp data. Methods: Euglycemic, hyperinsulinemic clamps were performed in 108 T1D adults (age (mean±SD) 34±7 yrs, T1D duration 10±4 yrs, HbA1c 7.7±1.5%; 33 with microvascular complications). Measured GDR (last 30min of the clamp) ranged 0.5 - 9.6 mg/kg/min (median (LQ, UQ) 4.45 (3.04, 6.5 mg/kg/min) were compared with eGDR and eLog10M/I calculated using simple formulae by (1) Williams, (2) Zheng, (3) Dabelea and (4) and (5) (Australia (AU)) authors, all derived from routine clinical chemistry and demographics. eGDR formula (Duca) was not assessed as it includes adiponectin levels. Results: Results are in Table 1. Conclusion: Authors (AU) formulae to estimate IS, including age, sex, HDL-C, BMI, HbA1c, pulse pressure and WHR had highest correlation with measured GDR and better performance (AUROC) in detecting low IS than other formulae. Disclosure A. S. Januszewski: None. P. Niedzwiecki: None. N. Sachithanandan: None. G. M. Ward: None. C. Karschimkus: None. D. N. O’neal: Advisory Panel; Self; Abbott Diabetes, Medtronic, Sanofi, Research Support; Self; Dexcom, Inc., GlySens Incorporated, Medtronic, Pacific Diabetes Technologies. D. Zozulinska-ziolkiewicz: None. A. Uruska: None. A. Jenkins: Advisory Panel; Self; Abbott Diabetes, Sanofi-Aventis, Other Relationship; Self; Amgen Inc., Research Support; Self; Abbott, International Diabetes Federation, JDRF, Medtronic, Mylan N. V.

Summary Dicer knockout mouse models demonstrated a key role for microRNAs in pancreatic β-cell function. Studies to identify specific microRNA(s) associated with human (pro-)endocrine gene expression are needed. We profiled microRNAs and key pancreatic genes in 353 human tissue samples. Machine learning workflows identified microRNAs associated with (pro-)insulin transcripts in a discovery set of islets (n = 30) and insulin-negative tissues (n = 62). This microRNA signature was validated in remaining 261 tissues that include nine islet samples from individuals with type 2 diabetes. Top eight microRNAs (miR-183-5p, -375-3p, 216b-5p, 183-3p, -7-5p, -217-5p, -7-2-3p, and -429-3p) were confirmed to be associated with and predictive of (pro-)insulin transcript levels. Use of doxycycline-inducible microRNA-overexpressing human pancreatic duct cell lines confirmed the regulatory roles of these microRNAs in (pro-)endocrine gene expression. Knockdown of these microRNAs in human islet cells reduced (pro-)insulin transcript abundance. Our data provide specific microRNAs to further study microRNA-mRNA interactions in regulating insulin transcription., Graphical abstract, Highlights • Unbiased machine learning workflow ranks miRNAs associated with insulin transcription • Forced expression of top-ranked miRNAs drives pro-endocrine program in progenitor cells • Knockdown of top-ranked miRNAs retards insulin gene transcription in human islets • Insulin transcript-associated miRNAs are reduced in islets of donors with type 2 diabetes, Pathophysiology; Computational Bioinformatics; Transcriptomics

Type 2 diabetes (T2D) is associated with increased risk of cardiovascular disease (CVD). As disturbed angiogenesis and endothelial dysfunction are strongly implicated in T2D and CVD, we aimed to investigate the association between a novel anti-angiogenic protein, FK506-binding protein like (FKBPL), and these diseases. Plasma FKBPL was quantified by ELISA cross-sectionally in 353 adults, consisting of 234 T2D and 119 non–diabetic subjects with/without CVD, matched for age, BMI and gender. FKBPL levels were higher in T2D (adjusted mean: 2.03 ng/ml ± 0.90 SD) vs. non-diabetic subjects (adjusted mean: 1.79 ng/ml ± 0.89 SD, p = 0.02), but only after adjustment for CVD status. In T2D, FKBPL was negatively correlated with fasting blood glucose, HbA1c and diastolic blood pressure (DBP), and positively correlated with age, known diabetes duration, waist/hip ratio, urinary albumin/creatinine ratio (ACR) and fasting C-peptide. FKBPL plasma concentrations were increased in the presence of CVD, but only in the non-diabetic group (CVD: 2.02 ng/ml ± 0.75 SD vs. no CVD: 1.68 ng/ml ± 0.79 SD, p = 0.02). In non-diabetic subjects, FKBPL was positively correlated with an established biomarker for CVD, B-type Natriuretic Peptide (BNP), and echocardiographic parameters of diastolic dysfunction. FKBPL was a determinant of CVD in the non-diabetic group in addition to age, gender, total-cholesterol and systolic blood pressure (SBP). FKBPL may be a useful anti-angiogenic biomarker in CVD in the absence of diabetes and could represent a novel CVD mechanism.

AIM: To measure skin autofluorescence in youth (

Introduction: Current ISPAD guidelines recommend biennial diabetic retinopathy (DR) screening starting at age 11 yrs with type 1 diabetes (T1D) duration 2-5 yrs. Growing evidence suggesting less frequent screening. Methods: DR was ETDRS graded and progress assed by Markov chain model analysis. Retinal photos were from 2,169 patients (baseline (mean±SD): age 13.1±2.1 yrs, HbA1c 8.5±1.4%, 5.4±2.9 yrs T1D, follow-up 5.3±3.6 yrs) who attended the T1D clinic at least twice in 1990-2018. Results: In 11/2,169 patients DR progressed to severe non-proliferative (SNP) DR or above. See tables 1 and 2 below for detailed results. Conclusions: Our data support less frequent DR screening in T1D youth without any DR. Although DR progression is generally slow, poor glycaemic control greatly accelerates it. Disclosure A.S. Januszewski: None. V. Velayutham: None. P.Z. Benitez-Aguirre: None. M.E. Craig: None. G. Liew: None. Y. Cho: None. A. Jenkins: Advisory Panel; Self; Abbott, Medtronic. Research Support; Self; Abbott, GlySens Incorporated, Medtronic, Sanofi-Aventis. K.C. Donaghue: None.

Background:Circulating microRNAs (miRNAs) may play a pathogenic role in acute coronary syndromes (ACS). It is not yet known if miRNAs dysregulated in ACS are modulated by colchicine. We profiled miRNAs in plasma samples simultaneously collected from the aorta, coronary sinus, and right atrium in patients with ACS.Methods:A total of 396 of 754 miRNAs were detected by TaqMan real-time polymerase chain reaction from EDTA-plasma in a discovery cohort of 15 patients (n = 3 controls, n = 6 ACS standard therapy, n = 6 ACS standard therapy plus colchicine). Fifty-one significantly different miRNAs were then measured in a verification cohort of 92 patients (n = 13 controls, n = 40 ACS standard therapy, n = 39 ACS standard therapy plus colchicine). Samples were simultaneously obtained from the coronary sinus, aortic root, and right atrium.Results:Circulating levels of 30 of 51 measured miRNAs were higher in ACS standard therapy patients compared to controls. In patients with ACS, levels of 12 miRNAs (miR-17, -106b-3p, -191, -106a, -146a, -130a, -223, -484, -889, -425-3p, -629, -142-5p) were lower with colchicine treatment. Levels of 7 of these 12 miRNA were higher in ACS standard therapy patients compared to controls and returned to levels seen in control individuals after colchicine treatment. Three miRNAs suppressed by colchicine (miR-146a, miR-17, miR-130a) were identified as regulators of inflammatory pathways. MicroRNAs were comparable across sampling sites with select differences in the transcoronary gradient of 4 miRNA.Conclusion:The levels of specific miRNAs elevated in ACS returned to levels similar to control individuals following colchicine. These miRNAs may mediate ACS (via inflammatory pathways) or increase post-ACS risk, and could be potentially used as biomarkers of treatment efficacy.

Background: In the FIELD trial, a 5-year randomized double-blind placebo-controlled trial of fenofibrate vs. placebo in 9,795 adults with type 2 diabetes (T2D), the only standard lipid parameter correlating with microvascular (renal) events was triglycerides. Given the high prevalence of stroke among diabetic patients, we explored associations between lipoprotein subfractions and risk for stroke in the FIELD trial. Methods: We performed ultracentrifugation using the vertical auto profile (VAP, Atherotech) on plasma (baseline and after 6 weeks of fenofibrate). Analyses were performed using Cox proportional hazards and logistic regression for new on-study events. Results were adjusted for gender and fenofibrate or placebo allocation. Results: HDL related analytes (HDL-C, HDL3-C, apo A1, apoA2) correlated with reduced risk for all stroke. LDL and its subfractions and Lp(a)-C did not. VLDL and its subfractions, non-HDL-C, triglycerides, apo B, apo En, various ratios incorporating apo C3, and the ratios of apoB/A1 and apoB/apoA2 all correlated with increased risk for stroke. Conclusions: VAP identifies multiple lipoprotein subclasses, apoproteins, and VAP subclass/apoprotein ratios associated with stroke. Many of these measures improved with fenofibrate therapy.

BACKGROUND: In people with type 1 diabetes (T1D), nocturnal hypoglycaemia (NH) can be slept through and can cause seizures, arrhythmias and death. Hypoglycaemia avoidance can induce hyperglycaemia and ketosis. Patient behaviour impacts clinical outcomes and may be changed by education. AIM: To develop and utilise a survey to evaluate patient self-management of overnight glycaemia in adults with T1D. METHODS: Adults with T1D attending two Australian tertiary referral diabetes clinics completed a survey about their diabetes self-management and glycaemic control, including responses to hypothetical pre-bed blood glucose (BG) levels (4-20 mmol/L). Statistical analyses included t-tests, Chi square tests and ANOVA with significance considered at P < 0.05. RESULTS: There were 205 participants (103 females), with a mean (SD) age of 41 (17) years, T1D duration of 20 (16) years, HbA1c of 7.8(1.4)%, (61.3(8.2) mmol/mol), 38% on insulin pump therapy (CSII) and 36% with impaired hypoglycaemia awareness (IHA). Mean (SD) number of BG tests/day was 5.4 (2.7). Patients set higher BG target levels at bedtime and overnight: 7.5(1.4) and 7.1(1.3) mmol/L, respectively, compared to daytime (6.9(1.0); P < 0.0001 and P = 0.002 respectively). Only 36% of participants reported treating nocturnal hypoglycaemia (NH) with the recommended refined, then complex, carbohydrate. Only 28% of patients made safe choices in all bedtime BG scenarios, with higher rates for CSII users, P = 0.0005. Further education was desired by 32% of respondents, with higher rates in those with (44%) versus without IHA (25%), P = 0.006. CONCLUSIONS: Many adults with T1D have suboptimal knowledge and behaviour regarding overnight BG self-management. A survey, piloted herein, may facilitate the identification of patients who could benefit from further education.

Background: Some country guidelines recommend that people with type 2 diabetes (T2D) limit their consumption of eggs and cholesterol. Our previously published 3-mo weight-maintenance study showed that a high-egg (≥12 eggs/wk) diet compared with a low-egg diet (

BACKGROUND It is not known whether circulating fibroblast growth factor 21 (FGF21) concentrations are associated with glycemic progression in patients with established type 2 diabetes. This study reports this relationship in type 2 diabetes patients participating in the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) trial. METHODS Plasma FGF21 was quantified in 9697 study participants. Among patients with lifestyle-only glucose control measures at baseline, glycemic progression was defined as the initiation of oral hypoglycemic agents or insulin therapy. We assessed the relationship of FGF21 concentrations with glycohemoglobin (Hb A1c), the homeostasis model assessment of β-cell function (HOMA-B) and insulin resistance (HOMA-IR), and glycemic progression. RESULTS Among 2584 patients with lifestyle-only glycemic therapy at baseline, plasma FGF21 concentrations were positively associated with HOMA-IR (5.1% increase per 100% increase in FGF21 concentrations). Patients with higher baseline plasma FGF21 concentrations had higher risk of glycemic progression over a 5-year period (P = 0.02), but the association was not significant after further adjusting for alanine aminotransferase (ALT) enzyme activity. During the fenofibrate active run-in phase, higher tertiles of fenofibrate-induced increase in FGF21 concentrations were associated with higher risk of glycemic progression (adjusted hazards ratio = 1.09 and 1.18 for tertiles 2 and 3, respectively, P for trend = 0.01), even after adjusting for ALT enzyme activity. This association was statistically significant in the fenofibrate group only (P = 0.01). CONCLUSIONS Higher baseline and fenofibrate-induced increase in FGF21 concentrations predict more rapid glycemic progression in type 2 diabetes patients. This association may be partly explained by hepatic function.

ObjectiveTo determine if continuous subcutaneous insulin infusion (CSII) therapy is associated with lower glycated haemoglobin (HbA1c) variability (long-term glycaemic variability; GV) relative to multiple daily injection (MDI) treatment in adults with type 1 diabetes mellitus (T1DM).DesignRetrospective audit.Setting and participantsClinic records from 506 adults with T1DM from two tertiary Australian hospitals.Outcome measuresLong-term GV was assessed by HbA1c SD and coefficient of variation (CV) in adults on established MDI or CSII therapy, and in a subset changing from MDI to CSII.ResultsAdults (n=506, (164 CSII), 50% women, mean±SD age 38.0±15.3 years, 17.0±13.7 years diabetes, mean HbA1c 7.8%±1.2% (62±13 mmol/mol) on CSII, 8.0%±1.5% (64±16 mmol/mol) on MDI) were followed for 4.1±3.6 years. CSII use was associated with lower GV (HbA1c SD: CSII vs MDI 0.5%±0.41% (6±6 mmol/mol) vs 0.7%±0.7% (9±8 mmol/mol)) and CV: CSII vs MDI 6.7%±4.6% (10±10 mmol/mol) vs 9.3%±7.3% (14±13 mmol/mol), both pConclusionsIn clinical practice with T1DM adults relative to MDI, CSII therapy is associated with lower HbA1c GV.

ContextSex hormone–binding globulin (SHBG) levels are associated with cardiovascular disease (CVD) risk factors. However, prospective data on the association between SHBG levels and CVD events are sparse, with conflicting results.ObjectivesTo examine associations between serum SHBG, total testosterone (TT), and incident CVD and CVD-related mortality in middle-aged to elderly men.Design and MethodsData on 2563 community-dwelling men (35 to 80 years) were obtained from participants in the Men Androgen Inflammation Lifestyle Environment and Stress cohort. The analytic sample included 1492 men without baseline (2002 to 2007) CVD and with fasted morning serum SHBG and TT available at both baseline and follow-up (2007 to 2010) and without medications affecting TT or SHBG. Associations of baseline SHBG and TT, with incident CVD and CVD mortality, were analyzed using logistic regression for incident CVD and Cox proportional hazard regression for CVD mortality, adjusting for established CVD risk factors.ResultsIn multivariable models, elevated baseline SHBG and lower baseline TT were independently associated with incident CVD (SHBG: OR, 1.54; 95% CI, 1.15 to 2.06 per SD increase in SHBG, P = 0.003; TT: OR, 0.71; 95% CI, 0.52 to 0.97 per SD decrease in TT; P = 0.03). A decrease in TT between time points was associated with incident CVD (OR, 0.72; 95% CI, 0.56 to 0.92; P = 0.01). Neither SHBG nor TT was significantly associated with all-age CVD mortality [hazard ratio (HR), 0.69; 95% CI, 0.29 to 1.63; P = 0.40; and HR, 0.60; 95% CI, 0.28 to 1.26; P = 0.18, respectively].ConclusionsAmong all men and men >65 years, elevated SHBG and lower TT were independently associated with both a greater risk of CVD and an increased CVD mortality risk.

Aim: Current guidelines recommend screening for retinopathy from 11 years in youth with type 1 diabetes (T1D) and 2-5 years T1D duration. We examined the longitudinal progression and regression of retinopathy in adolescents seen at our Diabetes Complications assessment service (DCAS) clinic. Methods: We analyzed digitized retinal photographs taken from 2000-2018 (n=814) in youth with >3 assessments. Retinopathy was graded using the modified Airlie house classification. Generalized estimating equations were used to explore the association between progression/regression and covariates (HbA1c, gender, and diabetes duration). Results: Mean age at baseline was 13.3+2.6 years, mean T1D duration 6.1+>3.4 years and mean follow- up 7.4 years. Retinopathy was present in 18.7% (n=152) at baseline assessment; with progression in 32.6% (n=266), regression in 7% (n=57) and persistence in 60.3% (n=491). Of those with progression, 185/266 (22.7%) had one step and 81 (9.9%) had > 2 step progression. Factors associated with retinopathy progression were HbA1c and T1D duration and for regression T1D duration (Table 1). Neither height nor SBP was significant for other outcomes. Conclusion: In adolescents with T1D, retinopathy persistence or progression was greater than of regression. Follow-up of into adulthood will inform the development of appropriate retinopathy screening schedules. Disclosure V. Velayutham: None. G. Liew: None. A.S. Januszewski: None. Y. Cho: None. P.Z. Benitez-Aguirre: None. M.E. Craig: None. A. Jenkins: Advisory Panel; Self; Abbott, Australian Diabetes Society, Medtronic. Research Support; Self; Abbott, GlySens Incorporated, Medtronic, Mylan. Speaker's Bureau; Self; Eli Lilly and Company, Novo Nordisk Inc. K.C. Donaghue: None.

Background: Haptoglobin (Hp) is a plasma protein with anti-oxidant, anti-inflammatory and pro-angiogenic properties. Based on the Hp gene alleles there are three Hp phenotypes (1-1, 2-1 and 2-2). In diabetes, Hp-2 is associated with substantially increased risk of cardiac and renal damage relative to Hp-1. AIMS: To evaluate 1) associations between Hp phenotype and levels; and 2) effects of fenofibrate vs. placebo on Hp levels. Methods: A substudy of 180 adults with type 2 diabetes (T2D) (50% females) from the FIELD trial. Average age was 60±6 years, BMI 30.4±5.1 kg/m2 and HbA1c 6.8±1.3%. Plasma (citrate) samples were evaluated at baseline, after 6-weeks daily 200 mg co-micronised fenofibrate (end of active run-in) and 2-years after randomisation to fenofibrate or placebo. Results: Hp phenotype 1-1 was detected in 19%, Hp 2-1 in 48% and Hp 2-2 in 33% subjects. Hp levels at baseline were 1.44±1.10, 1.31±0.49 and 0.99±0.46 mg/mL in type 1-1, 2-1 and 2-2 respectively (all p Conclusions: Hp levels differ by Hp phenotype in T2D adults. Fenofibrate lowers Hp levels in all phenotypes, however the effect is significantly attenuated in Hp 2-2. Disclosure A.S. Januszewski: None. H.K. Young: Other Relationship; Self; Medtronic. L. Li: None. R.L. OConnell: None. T. Lyons: None. C.B. Kelly: None. D. Sullivan: None. R. Scott: None. A.C. Keech: None. A. Jenkins: Advisory Panel; Self; Abbott, Australian Diabetes Society, Medtronic. Research Support; Self; Abbott, GlySens Incorporated, Medtronic, Mylan. Speaker’s Bureau; Self; Eli Lilly and Company, Novo Nordisk Inc. Funding Sydney Medical School Foundation; National Health and Medical Research Council of Australia

Background: Fenofibrate increases renal clearance of uric acid (UA). Relationships between baseline and short-term changes in plasma UA with fenofibrate and subsequent cardiovascular risk in patients with type 2 diabetes (T2D) are unknown. Method: Post hoc analyses of the FIELD trial explored the relationships between CVD events and 1) baseline UA level; and 2) short-term change in UA level over 6-week single-blind active fenofibrate run-in. Results: The FIELD trial showed 11% fewer cardiovascular events in patients with T2D assigned to fenofibrate compared to placebo over 5 years (HR = 0.89, 95% CI: 0.80-0.99, p = 0.035). Baseline UA (n=9622) ranged between 0.11 to 0.79 mmol/L (mean = 0.33, SD = 0.078). Each 0.1 mmol/L higher baseline UA increased CVD events by 21% (HR = 1.21 95% CI: 1.13-1.29, p < 0.001; Fig. 1A), and remained after adjusting for other classic risk factors (HR = 1.12, 95% CI: 1.04-1.21, p = 0.002). Fall in UA level with fenofibrate run-in also predicted lower CVD risk, adjusted for baseline UA and irrespective of trial treatment allocation (HR = 0.86, 95% CI: 0.76-0.97, p = 0.015; Fig. 1B). Discussion: Baseline and short-term fenofibrate-induced lowering of UA predict cardiovascular risk in patients with T2D, irrespective of long-term trial treatment allocation. The reduction in total CVD events with fenofibrate was not shown to be mediated through lowering of UA levels. Disclosure J.Y. Cao: None. B. Waldman: None. R.L. OConnell: None. D. Sullivan: None. V. Gebski: None. A.S. Januszewski: None. I. Marschner: None. R. Scott: None. M. Taskinen: Advisory Panel; Self; Novo Nordisk A/S. Consultant; Self; Akcea Therapeutics, Chiesi USA, Inc. Research Support; Self; Amgen Inc., Novo Nordisk A/S. Speaker’s Bureau; Self; Amgen Inc. R. Simes: None. N. McGill: None. A.J. Jenkins: Advisory Panel; Self; Abbott, Australian Diabetes Society, Medtronic. Research Support; Self; Abbott, GlySens Incorporated, Medtronic, Mylan. Speaker’s Bureau; Self; Eli Lilly and Company, Novo Nordisk Inc. A.C. Keech: None.

Background: In the FIELD trial, a 5-year randomized double-blind placebo-controlled trial of fenofibrate vs. placebo in 9,795 adults with type 2 diabetes (T2D), the only standard lipid parameter correlating with microvascular (renal) events was triglycerides. Given the high prevalence of diabetic microangiopathy, we explored associations between lipoprotein subfractions and nephropathy, retinopathy, microvascular amputations (MiAmp) and neuropathy. Methods: We performed ultracentrifugation using the vertical autoprofile (VAP, Atherotech) on plasma (baseline and after 6 weeks of fenofibrate). Analyses were performed using Cox proportional hazards and logistic regression for new on-study events. Results were adjusted for gender and fenofibrate or placebo allocation. Results: HDL related analytes (HDL-C, HDL3-C, apo A1, apoA2) correlated with reduced risk for neuropathy, nephropathy, and MiAmp. Buoyant LDL (LDL1-C) and densest LDL (LDL4-C) correlated negatively with neuropathy and positively for MiAmp, respectively. Triglycerides and apo C3 increased neuropathy and nephropathy risk. VLDL species correlated with increased MiAmp and retinopathy risk. Conclusions: VAP identifies multiple lipoprotein subclasses and VAP subclass/apoprotein ratios associated with diabetic microangiopathy. Many were improved with fenofibrate. Disclosure P.P. Toth: Consultant; Self; Amarin Corporation, Amgen Inc., AstraZeneca, Kowa Pharmaceutical Europe Co. Ltd., Novo Nordisk Inc. Speaker’s Bureau; Self; Amarin Corporation, Amgen Inc., Merck & Co., Inc., Novo Nordisk Inc., Regeneron Pharmaceuticals, Sanofi US. A.C. Keech: None. A.S. Januszewski: None. R.L. OConnell: None. L. Li: None. D. Sullivan: None. M. Taskinen: Advisory Panel; Self; Novo Nordisk A/S. Consultant; Self; Akcea Therapeutics, Chiesi USA, Inc. Research Support; Self; Amgen Inc., Novo Nordisk A/S. Speaker’s Bureau; Self; Amgen Inc. P.L. Drury: None. G.F. Watts: None. J.D. Best: Consultant; Self; Abbott. J. Ansquer: Research Support; Self; Abbott, Mylan. S.R. Jones: None. A.J. Jenkins: Advisory Panel; Self; Abbott, Australian Diabetes Society, Medtronic. Research Support; Self; Abbott, GlySens Incorporated, Medtronic, Mylan. Speaker’s Bureau; Self; Eli Lilly and Company, Novo Nordisk Inc.

Background: Glucose variability (GV) may be reflected by variation in either the short-term glucose levels (assessed by continuous glucose monitoring (CGM)) or the long-term by HbA1c or intermediate by 1,5-anhydroglucitol (1,5-AG). In patients with T1DM management by continuous subcutaneous insulin infusion (CSII) is usually associated with improved glycaemia compared to multiple daily insulin injections (MDI). Serum 1,5-anhydroglucitol (1,5-AG) correlates with GV on CGM in adult and pediatric T1D groups. It is not known whether CSII therapy without CGM improves intermediate GV. Methods: Blood was obtained from children (mean age 14.1 +/- 1.3 years) within 3-months of T1D diagnosis. Children were treated with CSII (n=12) or MDI (n=15) and followed for a further 1 to 3 time points (median, LQ-UQ 535, 519-563 days follow-up). GV was assessed measuring 1,5-anhydroglucitol (1,5-AG) (GlycoMark, Inc., Winston-Salem, NC). The mean difference, standard deviation (SD) and coefficient of variation (CV) of 1,5-AG and HbA1c was compared between treatment arms. Results: There was no difference between treatment modalities in baseline HbA1c (median, LQ-UQ 11.8, 10.2-13.5 % (105, 87-124 mmol/mol) vs. 12.6, 10.3-14.0 % (114, 89-130 mmol/mol) CSII vs. MDI) nor baseline 1,5-AG (median, LQ-UQ 2.8, 1.8-4.0 μg/mL vs. 3.6, 2.1-12.1 μg/mL CSII vs. MDI). 1,5-AG improved more (increased) in the CSII vs. MDI group (3.1 +/- 4.1 vs. -2.2 +/- 7.0 μg/ml respectively, P=0.029). This difference persisted following adjustment for the duration of follow-up. There was no significant difference in the HbA1c improvement between the CSII and MDI groups. There was no significant difference in the SD or CV of 1,5-AG or HbA1c between groups. Conclusions: Early use of CSII post-T1D-diagnosis in a pediatric population is associated with a higher 1,5-AG than with MDI therapy implying reduced glycaemic variability. Disclosure E.S. Scott: None. A.S. Januszewski: None. G. Fulcher: Advisory Panel; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Janssen Research & Development, Merck Sharp & Dohme Corp., Novo Nordisk Inc. Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Janssen Research & Development, Merck Sharp & Dohme Corp., Novo Nordisk Inc. Research Support; Self; Novo Nordisk Inc. T. Jones: Research Support; Self; Dexcom, Inc., Medtronic MiniMed, Inc. Speaker's Bureau; Self; Eli Lilly and Company, Roche Diabetes Care. E.A. Davis: None. A.J. Jenkins: Advisory Panel; Self; Abbott, Australian Diabetes Society, Medtronic. Research Support; Self; Abbott, GlySens Incorporated, Medtronic, Mylan. Speaker’s Bureau; Self; Eli Lilly and Company, Novo Nordisk Inc.

Background: The FIELD study, a 5-year randomized double-blind placebo-controlled trial of fenofibrate vs. placebo in 9,795 adults with type 2 diabetes (T2D), was designed to evaluate effects on coronary and cardiovascular (CV) events. In this analysis we explored associations between lipoprotein subfractions and on-study CV events and death. Methods: We performed ultracentrifugation using the vertical auto profile (VAP, Atherotech) on plasma at baseline and after 6 weeks of fenofibrate (active run-in) exposure. Analyses were performed using Cox proportional hazards and logistic regression analysis. Results were adjusted for gender, with log transformation as necessary. Results: Total CVD and CV death correlated negatively with HDL-C and its subfractions, as well as apoA1 and apoA2. In addition to LDL-C, small, dense LDL (LDL4-C), non-HDL-C, apo B, triglycerides, and apoC3 increased risk for total CVD. For CVD death, HDL-C and its subfractions were protective, while apo B, triglycerides, apo C3, and various VLDL-C species were associated with increased risk. Conclusions: Detailed lipoprotein analysis identifies multiple lipoprotein subclasses and apolipoproteins and their ratios associated with acute cardiovascular events and death. Serum levels of a number of these lipoprotein and apoprotein species were improved by fenofibrate therapy. Disclosure S.R. Jones: None. A.J. Jenkins: Advisory Panel; Self; Abbott, Australian Diabetes Society, Medtronic. Research Support; Self; Abbott, GlySens Incorporated, Medtronic, Mylan. Speaker’s Bureau; Self; Eli Lilly and Company, Novo Nordisk Inc. A.S. Januszewski: None. R.L. OConnell: None. L. Li: None. D. Sullivan: None. M. Taskinen: Advisory Panel; Self; Novo Nordisk A/S. Consultant; Self; Akcea Therapeutics, Chiesi USA, Inc. Research Support; Self; Amgen Inc., Novo Nordisk A/S. Speaker’s Bureau; Self; Amgen Inc. R. Scott: None. G.F. Watts: None. P.J. Barter: Advisory Panel; Self; Merck & Co., Inc., Pfizer Inc. R. Simes: None. P.P. Toth: Consultant; Self; Amarin Corporation, Amgen Inc., AstraZeneca, Kowa Pharmaceutical Europe Co. Ltd., Novo Nordisk Inc. Speaker’s Bureau; Self; Amarin Corporation, Amgen Inc., Merck & Co., Inc., Novo Nordisk Inc., Regeneron Pharmaceuticals, Sanofi US. A.C. Keech: None.

Introduction: Reviewing rCGM patterns may prompt lifestyle or therapeutic changes to achieve glycaemic targets but evidence for rCGM use in primary care management of T2D is limited. Methods: Two-arm RCT. Participants: Adults with T2D, HbA1c ≥0.5% above target, prescribed ≥2 non-insulin glycemia medications or insulin. Intervention: 1-hour diabetes education and (at 0/3/6/9/12 months): HbA1c assessment + wearing FreeStyle Libre Pro (Abbott) for up to 14 days prior to being discussed at a clinic visit. Physicians were trained in interpreting ambulatory glucose profiles. Control: 3-monthly ‘usual care’ clinic visits + r-CGM device worn (blinded, research data) at 0 and 12 months. Primary outcome: difference in mean HbA1c at 12 months. Secondary outcomes: mean differences in time in range (TIR: 4-10 mmol/L) and diabetes-specific distress (PAID) at 12 months, and HbA1c at 6 months. ITT analysis. Results: In 25 primary care practices, participants were: 299 adults with T2D, aged (mean(SD)) 60(10) years, HbA1c: 8.9(1.2)%, diabetes duration (median(IQR)) of 12(8,20) years. At 12 months, the between-group difference in mean HbA1c was 0.2% (p=0.112). The estimated mean percentage TIR was 8.4% higher in the intervention than the control arm (p=0.004). Diabetes-specific distress did not differ between arms (0.5; p=0.71). At 6 months, HbA1c was significantly lower in the intervention arm (0.5%; p Discussion: Use of 3-monthly rCGM in adults with T2D in primary care does not improve HbA1c at 12 months. We showed a statistically and clinically significant reduction in HbA1c at 6 months in the intervention group, as well as significant improvements in TIR at 12 months, with no change in diabetes distress. Our findings suggest the primary impact of r-CGM use on HbA1c in this setting is short term, and not associated with increase in the number of diabetes medications. Disclosure J. Furler: Research Support; Self; Abbott, Sanofi. D.N. O’Neal: None. J. Speight: Research Support; Self; AstraZeneca, Medtronic, Sanofi. Speaker’s Bureau; Self; Novo Nordisk A/S, Roche Diabetes Care. J.E. Manski-Nankervis: Research Support; Self; Australian National Health and Medical Research Council, Boehringer Ingelheim International GmbH, Diabetes Australia, Eli Lilly and Company. Speaker’s Bureau; Self; RACGP. S. Thuraisingam: None. E. Holmes-Truscott: Research Support; Self; Sanofi. Speaker’s Bureau; Self; Novo Nordisk Inc. K.R. De La Rue: None. L.E. Ginnivan: None. R.C. Doyle: None. K. Khunti: Advisory Panel; Self; Amgen Inc., AstraZeneca, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novo Nordisk A/S, Sanofi. Consultant; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Merck Sharp & Dohme Corp., Novartis AG, Novo Nordisk A/S, Pfizer Inc., Sanofi-Aventis, Servier, Takeda Pharmaceutical Company Limited. Research Support; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novartis AG, Novo Nordisk A/S, Pfizer Inc., Sanofi-Aventis. Speaker’s Bureau; Self; AstraZeneca, Berlin-Chemie AG, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Menarini Group, Merck Sharp & Dohme Corp., Novartis AG, Novo Nordisk A/S, Roche Pharma, Sanofi, Servier, Takeda Pharmaceutical Company Limited. M. Catchpool: None. K. Dalziel: None. J.I. Chiang: None. I. Blackberry: None. R. Audehm: Advisory Panel; Self; AstraZeneca, Novartis Pharmaceuticals Corporation. M. Kennedy: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Merck Sharp & Dohme Corp., Novo Nordisk Inc., Sanofi. M.J. Clark: None. A.J. Jenkins: Advisory Panel; Self; Abbott, Australian Diabetes Society, Medtronic. Research Support; Self; Abbott, GlySens Incorporated, Medtronic, Mylan. Speaker’s Bureau; Self; Eli Lilly and Company, Novo Nordisk Inc. A.S. Januszewski: None. D. Liew: Advisory Panel; Self; AstraZeneca, Bayer AG. Research Support; Self; AbbVie Inc., AstraZeneca, Bristol-Myers Squibb Company, CSL Behring, Pfizer Inc. P.M. Clarke: None. J.D. Best: Consultant; Self; Abbott. Funding National Health and Medical Research Council of Australia (APP1104241); Sanofi Australia; Abbott Diabetes Care

Objective: Contrasting findings exist regarding the associations between circulating sex hormone-binding globulin (SHBG) and total testosterone (TT) with type 2 diabetes (T2D) and cardiovascular diseases (CVD) in men. We examined prospective associations of SHBG and TT with incident T2D and CVD, in a cohort of community-dwelling men. Methods: Participants were aged 35 years and over at enrolment (n=2563) and followed for an average of 4.95 years. This analysis included men without T2D (1597) or CVD (1492) at baseline, and with fasted morning serum SHBG (chemiluminescent immunoassay) and TT (LCMSMS) at both time points, and without meds affecting TT or SHBG. T2D was identified by either self-report, fasting glucose (≥7.0 mmol/L), HbA1c (≥ 6.5%) and/or prescriptions for diabetes medications. CVD was ascertained by self-report and/or hospital data linkage. Logistic binomial regressions were used to assess associations between SHBG and incident T2D & CVD, adjusting for self-reported psycho-social, demographic and health status and related behavioural factors; measured waist circumference, HBA1c and plasma glucose, triglycerides, high-sensitivity C-reactive protein. Sensitivity analyses assessed mediation effects of anxiety, sleep duration, shift work ≥3years, and obstructive sleep apnoea (OSA). Results: During an average follow-up of 4.95 years, 14.5% (n=232) and 6.7% (n=101) of men developed T2D and CVD, respectively. Baseline TT was independently associated with incident T2D (odds ratio (OR) =0.72, 95%CI= [0.57, 0.92], P=0.01). An inverse association of baseline SHBG levels with incident T2D (OR=0.77 [0.62, 0.95], P=0.02), was insignificant after adjustment for TT (OR=0.91 [0.71, 1.17], P=0.48 for SHBG. Baseline TT (OR=0.71 [0.52, 0.98], P=0.04) and SHBG (OR=1.54 [1.15, 2.06], P=0.003) were independently associated with incident CVD. A decrease in TT between time points was associated with incident T2D (OR=0.81 [0.68, 0.97], P=0.02) and CVD (OR=0.72 [0.56,0.92], P=0.01). There was no association between ΔSHBG and incident T2D and CVD. In the sensitivity analyses there was evidence for mediation effects of shift-work on the association of TT, but not SHBG with CVD (both baseline &change models), and of longer sleep duration, OSA and shift work on the association of TT with T2D (change TT model only). Conclusions Shift-work mediates associations of TT with CVD. All sleep parameters had mediation effects on the association of decreasing TT with T2D. Funding: NH&MRC Unless otherwise noted, all abstracts presented at ENDO are embargoed until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. Abstracts presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.

Background Higher plasma fibroblast growth factor 21 (FGF21) levels predict incident cardiovascular events in type 2 diabetes patients. However, whether FGF21 levels predict cardiovascular events in statin-treated patients in the general population is unknown. We investigated whether FGF21 levels predict major cardiovascular event (MCVE) in the Treating to New Targets (TNT) trial participants. Methods After 8-week run-in on atorvastatin 10 mg/day, 10,001 patients with stable coronary disease in the TNT trial were randomized to 10 mg or 80 mg/day of atorvastatin for a median of 4.9 years. We analyzed data from 1996 patients with plasma FGF21 levels measured at randomization. Among them, 1835 patients had FGF21 measured one-year post-randomization. Results Higher ln-transformed FGF21 levels at randomization were associated with higher risk of incident MCVE (adjusted hazards ratio per SD increase = 1.18, P = 0.019). At 1-year post-randomization, FGF21 levels were lower in patients randomized to receive 80 mg versus 10 mg atorvastatin (186.9 versus 207.5 pg/mL respectively, P = 0.006). Higher ln-transformed FGF21 levels at 1-year post-randomization were also associated with higher subsequent risk of MCVEs (adjusted hazards ratio per SD increase = 1.24, P = 0.009). However, changes in FGF21 levels over 1-year were not related to subsequent MCVE risk. FGF21 levels had significant incremental value in net reclassification improvement in MCVE risk prediction. Conclusions Higher plasma FGF21 levels are associated with higher CVD risk in statin-treated high-risk patients. Higher dose atorvastatin is associated with a reduction in FGF21 levels. FGF21 provides incremental value in CVD risk prediction in statin-treated patients.

Introduction: Neutrophil elastase (NE) and proteinase 3 (PR3) are novel inflammation biomarkers. We investigated their associations with chronic complications, determinants of biomarker levels and effects of fenofibrate in patients with type 2 diabetes mellitus (T2DM) from Fenofibrate Intervention and Event Lowering in Diabetes study. Methods: Plasma NE and PR3 levels were quantified at baseline ( n = 2000), and relationships with complications over 5-years assessed. Effects of fenofibrate on biomarker levels ( n = 200) were determined at four follow-up visits. Results: Higher waist-to-hip ratio, homocysteine and C-reactive protein and lower apoA-II were determinants of higher NE and PR3 levels. Higher NE levels were associated with on-trial stroke and cardiovascular mortality, and higher PR3 levels with on-trial stroke, but associations were not significant after adjustment for confounding factors. Although higher NE and PR3 levels were associated with baseline total microvascular disease, only NE levels were associated with on-trial neuropathy or amputation. These associations were not significant after adjusting for multiple comparisons. NE and PR3 levels did not change with fenofibrate. Conclusions: In T2DM plasma NE and PR3 levels are associated with vascular risk factors, and total microvascular disease at baseline, but on rigorous analyses were not associated with on-trial complications. Levels were not changed by fenofibrate.

Reported associations between liver enzymes and mortality may not hold true in type 2 diabetes, owing to a high prevalence of non-alcoholic fatty liver disease, which has been linked to cardiovascular disease and mortality in its own right. Our study aimed to determine whether alanine aminotransferase (ALT) or γ-glutamyl transferase (GGT) levels predict mortality in type 2 diabetes, and to examine possible mechanisms.Data from the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study were analyzed to examine the relationship between liver enzymes and all-cause and cause-specific mortality over 5years.Over 5years, 679 (6.9%) individuals died. After adjustment, for every standard deviation increase in ALT (13.2U/L), the HR for death on study was 0.85 (95% CI 0.78-0.93), p0.001. Conversely, GGT70U/L, compared with GGT ≤70U/L, had HR 1.82 (1.48-2.24), p0.001. For cause-specific mortality, lower ALT was associated with a higher risk of cardiovascular death only, whereas GGT70U/L was associated with higher risks of death due to cardiovascular disease, cancer and non-cancer/non-cardiovascular causes. The relationship for ALT persisted after adjustment for indirect measures of frailty but was attenuated by elevated hsCRP.As in the general population, ALT has a negative, and GGT a positive, correlation with mortality in type 2 diabetes when ALT is less than two times the upper limit of normal. The relationship for ALT appears specific for death due to cardiovascular disease. Links of low ALT with frailty, as a potential mechanism for relationships seen, were neither supported nor conclusively refuted by our analysis and other factors are also likely to be important in those with type 2 diabetes.